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Publications

Journal Article Epublish

PubMed: 41995076 DOI: 10.7554/eLife.107332

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle.

Elife 14

Authors: Yibo Fan, Senuri De Silva, Nishat I Tabassum, Xiangyuan Peng, Vernise J T Lim, Xiangru Cheng, Keshava K Datta, Rohan Lowe, Terrance G Johns, Mark P Mattson, Suresh Mathivanan, Christopher G Sobey, Eitan Okun, Yong U Liu, Guobing Chen, Mitchell Kim Peng Lai, Dong-Gyu Jo, Jayantha Gunaratne, Thiruma V Arumugam

Affiliations

  • Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Australia. La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
  • Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, Australia.
  • La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
  • La Trobe University-Proteomics and Metabolomics Platform (LTU-PMP), La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
  • Epigenes Australia Pty Ltd, Melbourne, Australia.
  • Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
  • Centre for Cardiovascular Biology and Disease Research, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Australia.
  • Baker Heart and Diabetes Institute, Melbourne, Australia.
  • The Paul Feder laboratory for Alzheimer's disease research at the Mina and Everard Goodman Faculty of Life Sciences, and the Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel.
  • Laboratory for Neuroimmunology in Health and Disease, Center for Medical Research on Innovation and Translation, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
  • Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China.
  • Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
  • Translational Biomedical Proteomics Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
  • Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Abstract

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

MeSH

Up-Regulation, Fasting, Muscles, Biological Science Disciplines, Cerebral Cortex, Brain, Liver, Cell Biology, Cholesterol, Proteomics, Down-Regulation, Tissues, Fatty Acids, Intermittent Fasting